GP - Clinics 2020 07

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Vol 11 No 4, July, 2020 A CME Journal for Family Physicians

Empowering Your Practice
Online
14 Ocular Manifestations of Diabetes
Abridged
Version
31 A Family With a Variety of “Flu” Symptoms
33 Vitamin D Supplements Don't Prevent Cancer or

Evidence-Based Heart Disease
Consultations
In Primary
38 Can Drugs Be Used Past Their Expiration Date?
Care
20 COVID Round Up 25 Spot The Diagnosis 27 X-Ray Tutorial 35 What’sYour Diagnosis?

22 Legal Pearls 26 Q and A 30 FDA Alerts 37 Image Diagnosis
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,1,2 10 APR 2020
IND2134908
For the use of Chemists Only
*as compared to other laxatives | Images shown are not of actual patients and are for representational purpose only
Ref.: 1. Sfetcu N. Health and drugs: Disease, prescription and medication. 2014 Laxatives | 2. Portalatin M, Winstead N. Medical
management of constipation. Clin Colon Surg. 2012;25(1):12-19 5. Fred F. Frerri,s clinical advisor. Elsevier Health Science 2016. Pg no
1567 | 3. Patankar R. and Mishra A. A prospective and non-comparative study to assess the effectiveness and safety of combination
laxative therapy containing milk of magnesia, liquid paraffin, and sodium picosulphate(Cremaffin-Plus@) in the management of
constipation in patients with anal fissures/hemorrhoids/ obstructive defecation syndrome. Int Surg J 2017;4:3899-906. | 4. Data on file
For the use of a Registered Medical Practitioner or a Hospital or Laboratory only

Liquid Paraffin, Milk of Magnesia & Sodium Picosulfate Oral emulsion
CREMAFFIN PLUS
COMPOSITION: Each 5 ml (1 teaspoonful approx.) contains: | Liquid Paraffin I.P. 1.25 ml | Milk of Magnesia I.P. 3.75 ml | Sodium Picosulfate B.P. 3.33 mg | Colours: Carmoisine & Ponceau 4R | INDICATION: For the
symptomatic relief of constipation in adults. | DOSAGE AND ADMINISTRATION: Adults and children over 12 years: 7.5 ml (approx. 1½ teaspoonful) if the response is unsatisfactory, the dose may be increased to 15 ml (3
teaspoonful) or as advised by the physician. | Children 5 to 12 years 1 teaspoonful or as advised by the physician. | Children 3 to 5 years As advised by the physician. | Children under 3 years Not recommended |
Cremaffin Plus is best taken at bedtime preferably with water. Elderly: There is no need for dosage reduction in the elderly. | CONTRAINDICATIONS: Patients with hypersensitivity to liquid paraffin, magnesium hydroxide or
sodium picosulfate. Presence of intestinal obstruction, ileus, toxic megacolon gastric retention abdominal pain, nausea or vomiting, and in children under 3 years of age, patients with severely reduced renal function |
WARNINGS AND PRECAUTIONS: In patients with renal impairment, Cardiac Arrhythmias, Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis, Use in Patients with Significant Gastrointestinal Disease.
Prolonged use is not recommended. | PREGNANCY AND LACTATION: The safety of Cremaffin Plus for use in pregnancy and lactation is not established. Therefore, as with other medicines, Cremaffin Plus should not be
administered during pregnancy and lactation. | ADVERSE REACTIONS: Liquid paraffin may cause anal seepage and irritation, granulomatous reactions. Nausea, headache, and vomiting are the most common adverse
reactions (> 1%) reported with sodium Picosulfate and milk of magnesia. Abdominal pain, diarrhea, fecal incontinence, and proctalgia have been reported with sodium picosulfate. | OVERDOSAGE: Gastric lavage may be
performed where appropriate. Treatment should be symptomatic and supportive. | Issued on: 5th Nov 2018 | Source: Prepared based on full prescribing information version v3.0, dated: 29th Oct 2018 | ®Trademark of the
Abbott Group of Companies. For full prescribing information, please contact: Medical Sciences Division, Abbott India Limited, Floor 17, Godrej BKC, Plot No. C – 68, BKC, Near MCA Club, Bandra (E), Mumbai – 400 051.
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FEATURE 14
OCULAR MANIFESTATIONS OF DIABETES

Leonid Skorin Jr, DO, OD, MS
Mayo Clinic Health System in Albert Lea, MN.
Kirsten Krein, BS
Pacific University College of Optometry in Forest Grove, OR.
Feature, 14
COVID Round Up 20
Coronavirus Developments Around The World
21 Existing Drugs, Respiratory Droplets

Michael Potts
New Data Indicate Remdesivir May Reduce Hospital Stay
Christina Vogt
Covid Roundup, 20
Legal Pearls 22
Law Prespective In Medicine
The Folly of Ordering, Then Ignoring, Radiographs

Ann W. Latner, JD
Legal Pearls, 22
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Spot The Diagnosis 25
Test Your Diagnostic Skills In Dermatology
Quiz #34
Q&A 26
Spot The Diagnosis, 25
An Interaction With Experts
How Important is Glucagon in the Pathophysiology of Diabetes?

Kim A. Carmichael, MD, FACP—Series Editor.
X-Ray Tutorial 27
The Key To Interpreting X-Ray
Retrocardiac Mass
FDA Alerts 30
Be The First To Know To Practice
FDA Approves New Option for Heavy Menstrual Bleeding
FDA Alerts, 30
FDA Expands Use for Antibiotic
WHAT’S THE “TAKE HOME”? 31

Clinical Evidence From Doctors’ Clinic
A Family with a Variety of “Flu” Symptoms

Ronald Rubin, MD—Series Editor
Temple University, USA
Nutritional Pearls, 33
Contd. ...

Nutritional Pearls 33
Nutrition and Health
Vitamin D Supplements Don't Prevent Cancer or Heart Disease

Timothy S. Harlan, MD
What's Your Diagnosis?, 35

WHAT’S YOUR DIAGNOSIS? 35
Sharpen Your Physical Diagnostic Skills
Multiple Cutaneous Nodules in a Previously Healthy Male

Alix Mitchell, MD, and David Effron, MD—Series Editor
IMAGE DIAGNOSIS 37
Self – Test Your Diagnostic Acumen
Disappearing Digits: Metabolic Bone Disease in End-Stage

Renal Disease
Shitij Arora, MD, FACP and Fathima Jahufar, MD
Bronx, NY.
Drugs In Practice 38
Image Diagnosis, 37 Critical Review of Drugs Used in Daily Practice
Drugs Past Their Expiration Date
Peanut Allergen Powder
Contd. ...
International Editorial Board Editorial Board
MICHAEL J. BLOCH, MD LAWRENCE I. KAPLAN, MD GREGORY W. RUTECKI, MD

Medical Director, Vascular Care Assistant Dean for Clinical Education Staff Physician
Renown Institute for Heart and Professor of Medicine National Consultation Service
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University of Nevada Reno School of Medicine Philadelphia, Pennsylvania Cleveland, Ohio
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University of Michigan Medical School Lewis Katz School of Medicine at Temple
Ann Arbor, Michigan University
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William J. Brady, MD Cardiology, Emergency Medicine Mary P. Maiberger, MD Dermatology
Kim A. Carmichael, MD Endocrinology James Matera, DO Nephrology
TS Dharmarajan, MD Internal Medicine, Geriatrics David T. Nash, MD Cardiology
David Effron, MD Emergency Medicine Eileen O’Grady, PhD, RN, NP Wellness
Pamela Ellsworth, MD Urology Michael Picco, MD Gastroenterology
Abimbola Farinde, PharmD, MS Pharmacology David M. Quillen, MD Family Medicine
Steven R. Feldman, MD, PhD Dermatology Syed A. A. Rizvi, PhD Internal Medicine
Ty J. Gluckman, MD Cardiology Anamaria Shanley, MSN, ARNP-BC Neurology
John W. Harrington, MD Pediatrics Leonid Skorin Jr, DO, MS Ophthalmology
Jorge L. Herrera, MD Hepatology Todd P. Stitik, MD Physical Medicine
Sheldon P. Hersh, MD Otolaryngology Michael B. Strauss, MD Orthopedics
Jonathan S. Ilowite, MD Pulmonology Michael H. Weisman, MD Rheumatology
Saundra Jain, MA, PsyD, LPC Psychology James T. Willerson, MD Cardiology
Deepak M. Kamat, MD, PhD Pediatrics Barbara B. Wilson, MD Dermatology
David L. Kaplan, MD Dermatology Golder N. Wilson, MD, PhD Genetics, Pediatrics
Alexander K. C. Leung, MD Pediatrics William Yaakob, MD Radiology
Samuel Louie, MD Pulmonology
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CONTENTS:
1. Introduction
Title: Ready Reckoner for Medical
Officers – Adverse Drug Reactions
2. De�nitions
Associated with Anti-Tubercular 3. Adverse Reactions to Anti-TB Drugs
Drugs Identi�cation & 4. Division of AIDS (DAIDS) Grading for Severity of Adverse Events
Management 5. Risk Factors for ADRs
6. Steps for Early Identi�cation of ADRs
Pages: 56 7. Danger Signs/Symptoms for Immediate Referral to Higher Centre
8. Mechanism for Referral to Higher Health Facility for Management of ADRs
Developed by: The Union South East Asia 9. Referral Mechanism and Flow
10. Drugs Recommended for Managing ADRs due to Anti-TB drugs
11. Management of Adverse Drug Reactions ADRs
12. Management of Common ADRs
13. Recording and Reporting
14. Monitoring Indicators
15. Patient Centric Care
Title: Approach to Pediatric Patients in Clinical Practice for GPs, Vol 1 / Vol 2 (with CME Q&A after each chapter)
Author: Dr YK Amdekar, MD, DCH, FRCPCH
Consultant Pediatrician, Mumbai
Pages: Vol 1 (140), Vol 2 (136) Publisher: clinicsindia Language: English Dimensions: 0.25 x 5.5 x 8.25 inches; paperback
CONTENTS: Volume 1 Volume 2
1. Fever in Children: Friend or Foe? 1. Anemia: Most Common Nutritional Deciency
2. Cough: A Distressing Symptom to a Child and a 2. All That Wheeze is not Asthma And All Asthmatics
Challenge to a Physician Don’t Wheeze
3. Acute Diarrhea in Children: How to Stop? 3. Pneumonia: Still a Great Childhood Killer
4. How to Keep a Crying Child Quiet? 4. Tuberculosis: An Unconquered Disease
5. Testing a Diagnostic Test 5. Jaundice: A Symptom And Not A Disease
6. Vaccines: Which Ones Are the Best? 6. The Importance of Monitoring Growth and
7. How to Identify a Seriously ill Child? Development?
8. When Do Antibiotics Fail? 7. Feeding Issues In Children
9. Tonics: For Whom and When? 8. What You Should Know About Neonates
10. Impending Obesity Epidemic in India 9. Urinary Tract Infection: Take It Seriously
11. Autism Spectrum Disorder: Increasing Awareness 10. Convulsions in Children: An Easy Approach
or Higher Prevalence? 11. Bleeding Disorders in Children
12. Adolescence: A Tricky Period 12. Arthritis In Children
Title: Let’s Talk TB (with CME Q&A after each chapter); Third Edition, 2018
Author: Prof (Dr) Madhukar Pai, MD, PhD;
Canada Research Chair in Translational Epidemiology & Global Health at McGill University, Montreal.
Director of McGill Global Health Programs, and Associate Director of the McGill International TB Centre.
Pages: 104 Publisher: clinicsindia Language: English Dimensions: 0.25 x 7.75 x 10.75 inches; paperback
CONTENTS 1. Diagnosis of Pulmonary Tuberculosis: What Every GP Should Know
2. Diagnosis of Tuberculosis: Importance of Appropriate Specimen Collection
3. Interpretation of Chest X-rays in Tuberculosis
4. Improving Access to Aordable and Quality TB Tests in India
5. Treatment of Pulmonary Tuberculosis: What Every GP Should Know
6. Extrapulmonary Tuberculosis: New Diagnostics and New Policies
7. Management of Latent Tuberculosis Infection
8. Management of HIV and Tuberculosis: What Every GP Should Know
9. Management of Drug-Resistant Tuberculosis: Q&A for Primary Care Physicians
10. Childhood Tuberculosis: Q&A For Primary Care Physicians
11. Management of Tuberculosis: 10 Common Pitfalls To Avoid
12. What Counselling and Support Do Patients With Tuberculosis Need?
13. Call To Action For A TB-Free India
14. Adverse Drug Events With Anti Tuberculosis Therapy: What Every GP Should Know
15. Drug-Resistant Tuberculosis: 10 Principles for Effective Management
16. Monitoring and Improving Adherence to Tuberculosis Medications
17. Nutritional Care and Support of Patients WithVol
Tuberculosis
11 No 4, in India:
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2020 General Physicians
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18. India’s Ambitious New Plan to Conquer TB Needs Cash and Commitment
OCULAR
MANIFESTATIONS
OF DIABETES
ABSTRACT: Nearly half of Americans with diabetes have diabetic retinopathy, the leading cause of new cases of blindness in Americans
under age 74. Despite evidence that tighter control of blood glucose and blood pressure reduces the risk of microvascular diabetes
complications, as well as significant advances in the clinical management of diabetic eye disease, rates of diabetic retinopathy in the
United States have increased 89% over the last decade. This article reviews the risk factors and ocular signs of diabetic retinopathy.
Current concepts in therapy of diabetic retinopathy are also presented.
Leonid Skorin Jr, DO, OD, MS, is an ophthalmologist at Kirsten Krein, BS, is a fourth-year optometry student at Pacific
the Mayo Clinic Health System in Albert Lea, MN. University College of Optometry in Forest Grove, OR.
D
iabetes mellitus is a chronic disease with long-term mac- This is thought to be due to both better detection and increas-
rovascular and microvascular complications. Included in ing rates of diabetes.2 Diabetes is the leading cause of new onset
these complications is diabetic retinopathy. Diabetic reti- blindness for people aged 20 to 74 years.3 The CDC have indi-
nopathy is often asymptomatic, but may be evident early cated that 11% of people with diabetes have some form of vi-
in the disease process. The National Eye Institute (NEI) reports sual impairment with 3.8% having uncorrectable visual pathol-
that nearly half of people (40%-45%) with diabetes have ogy.4 Significantly higher rates of sight-threatening diabetic
diabetic retinopathy.1 The NEI estimates that 7.7 million peo- retinopathy occur among African, Latino, and Native American
ple aged 40 and older have some degree of diabetic eye dis- populations.5 The duration of diabetes is the major risk factor
ease.1 That represents an 89% increase since 2000, and projec- for the development of diabetic retinopathy. Longitudinal stud-
tions anticipate another jump of 75%, to 13.5 million, by 2020.1 ies found that retinopathy develops within 5 years of diagnosis
27014 CONSULTANT
GP Clinics •Vol
April
11 2015 • www.consultant360.com
No 4, July, 2020
Ocular Manifestations
of Diabetes
of diabetes in about 25% of people with Legend Color names in parentheses indicate color of the arrow in the corresponding figure.
type 1 diabetes, 40% of people with type

2 diabetes who are taking insulin, and 24%
of people with type 2 diabetes who are
not taking insulin.6 Patients with poor
glycemic control and uncontrolled hyper-
tension are at greater risk than those with
good control of these factors.7,8
HOW DIABETES AFFECTS THE EYE

There are many proposed mechanisms
for how diabetes affects the eye; however,
the exact mechanism is not fully under-
stood. Proposed mechanisms contribut-
ing to the microvascular damage in dia-
betes include the direct toxic effects of
hyperglycemia, sustained alterations in
cell signaling pathways, and chronic mi-
crovascular inflammation with leukocyte-
mediated injury.9 Whatever the mecha-
nism or combination of mechanisms, the
end result is retinal blood vessel leakage, Figure 1. Proliferative diabetic retinopathy illustrating microaneurysms (pink) and
hemorrhaging, and ischemia. preretinal hemorrhaging (yellow).
Other common nonretinal findings
and symptoms of diabetic eye disease in-
clude fluctuations of refractive errors
when glucose from the aqueous and vit-
reous diffuse into the natural lens. In
cases of proliferative diabetes, neovascu-
larization of the iris and anterior cham-
ber angle can lead to the development of
neovascular glaucoma. Extraocular mus-
cle palsies cause diabetics to have diplo-
pia. Premature cataracts and papillopathy
of the optic nerve lead to blurred vision
or even significant sight loss.10
CLASSIFICATIONS
The following are classifications of dia-
betic retinopathy according to the Early
Treatment Diabetic Retinopathy Study
(ETDRS). The ETDRS scale is the gold
standard from which a number of other
Figure 2. Fundus photograph of moderate nonproliferative diabetic retinopathy
grading scales have been adapted.11
illustrating examples of a flame-shaped intraretinal hemorrhage (yellow), multiple
Nonproliferative diabetic retinopathy
hard exudates (green), cotton wool spots (magenta), and blot-shaped intraretinal
(NPDR) is characterized by the presence
hemorrhages (blue).
of hemorrhages and/or microaneurysms,
hard exudates, cotton wool spots (white, down into mild, moderate, and severe Diabetic macular edema (DME) can
fluffy-appearing patches occurring in forms of NPDR. occur independently or in addition to
edematous areas of the retina), intraretinal Proliferative diabetic retinopathy either NPDR or PDR. DME is diag-
microvascular abnormalities (IRMA; ab- (PDR) occurs when there is significant nosed by retinal thickening and hard ex-
normal communication between arteri- retinal ischemia and requires the presence udates in the macular area. DME is the
oles and venules), and venous beading. of neovascularization on the retinal sur- leading cause of vision loss in type 2 dia-
This category can be further broken face or a vitreous/preretinal hemorrhage. betics.12 To diagnose DME, the clinician

of Diabetes
litus type 1 develop DME within 9 years

of diabetes onset.14 For type 2 diabetes
mellitus insulin-dependent patients, the
10-year incidence of proliferative reti-
nopathy is 25.4% and for diabetes melli-
tus type 2 noninsulin-dependent indi-
viduals, that figure is 13.9%.14 Because
almost 26 million children and adults in
the United States have diabetes, a large
number of patients are at risk for DME.15
OCULAR SIGNS OF DIABETIC RETINOPATHY

Often, 1 of the first ocular signs of dia-
betes is microaneurysms. These occur as a
result of weakened capillary walls, predis-
posing the small retinal vessels to leakage
(Figure 1). Microaneurysms can be diffi-
cult to see, even with the high magnifica-
tion of direct ophthalmoscopy. Fluorescein
angiography (FA) may be necessary to
Figure 3. Proliferative diabetic retinopathy illustrating neovascularization (green) truly visualize microaneurysms. FA is a
and cotton wool spots (blue). Also noted is hard exudate scattered throughout the procedure in which fluorescent dye is in-
macular area (yellow). jected into the bloodstream and a series of
photographs are taken with a retinal cam-
era to evaluate the blood flow to the reti-
na and choroid. FA is indicated when
there is suspicion that a patient has neo-
vascularization of the retina or disc and/or
when DME is suspected. Intraretinal
hemorrhages are another sign of diabetic
retinopathy. They are referred to as dot/
blot or flame-shaped hemorrhages be-
cause of their appearance. Their appear-
ance is dictated by their location within
the retina. Dot/blot hemorrhages occur in
the inner layers of the retina, so the blood
is spread out vertically and appears to be
confined to a small area (Figures 2, 3,
4A, and 4B). Flame-shaped hemorrhages
are located within the tightly packed
nerve fiber layer. The blood spreads hori-
zontally across the retina within this layer,
giving the hemorrhage an elongated
Figure 4A. Fundus photographs post-panretinal photocoagulation treatment.
flame-shaped appearance (Figure 2). Cot-
Multiple laser scars (yellow), cotton wool spots (blue), and blot-shaped intraretinal
ton wool spots are areas of the retina that
hemorrhages (purple).
have become ischemic and consequently,
has to view the macula in 3-D. Unfortu- the development and progression of dia- turned a white or yellow color (Figures
nately, the view obtained using a direct betic retinopathy.13 The Diabetes Control 2, 4A, and 4B). They represent localized
ophthalmoscope is not adequate to diag- and Complications Trial (DCCT) found nerve fiber layer swelling secondary to ob-
nose DME. that in patients with type 1 diabetes mel- structed axoplasmic flow.16
litus for 30 years the cumulative inci- Hard exudates are lipid residues of se-
RISK FACTORS FOR DIABETIC RETINOPATHY dence of proliferative retinopathy was rous leakage from damaged capillaries and
Blood glucose control is the single 50%.14 The DCCT also reported that breakdown of the blood-retina barrier.17
most important modifiable risk factor for nearly 27% of patients with diabetes mel- They appear as yellow-colored deposits

of Diabetes
with sharp margins (Figures 2, 3, and 5).

They can occur singularly or as a circi-
nate ring.16 If they are present in a circu-
lar pattern, it is safe to assume there has
been, or is currently, swelling of the retina
within the borders of the hard exudate
(Figure 3).
Venous beading in the retina appears as
bulges in the wall of a retinal vein, giving
the vessel a beaded or sausage link appear-
ance (Figure 5).Venous beading is seen in
the presence of increasing nonperfusion
and is highly associated with the risk of
PDR developing. IRMA are shunt vessels
and appear as abnormal branching or dila-
tion of existing blood vessels within the
retina that act to supply areas of nonperfu-
sion (Figure 3). Neovascularization can
occur anywhere in the eye. If it is present
along the pupillary ruff or other areas of Figure 4B. Red-free view of retina post-panretinal photocoagulation treatment.
the iris, it is referred to as neovasculariza- Note how much easier it is to see cotton wool spots and hemorrhages on viewing
tion of the iris (Figure 6). If it occurs with the red free filter.
anywhere on the optic disc or if an area of
neovascularization is within 1 disc diam-
eter of the optic disc it is referred to as
neovascularization of the disc (Figures
7A and 7B). Neovascularization of any
size found elsewhere in the retina, greater
than 1 disc diameter away from the optic
disc is referred to as neovascularization
elsewhere (Figure 5). Neovascularization
and IRMA can be easily confused. Neo-
vascularization has a much finer appear-
ance when compared to IRMA and will
leak when tested with FA, whereas IRMA
vessels will not. In addition, IRMA lies
within the retina and does not form ab-
normal attachments to the vitreous while
neovascularization frequently does.16
These ocular signs are not necessarily
in order of presentation. Although micro-
aneurysms are almost always present if
other signs of diabetes are visualized, it Figure 5. Proliferative diabetic retinopathy showing dense preretinal hemorrhaging
does not mean that hemorrhages must be (yellow) and prominent venous beading (purple).
present before cotton wool spots or that
IRMA only occurs if hard exudates have MANAGEMENT for macular edema and binocular indirect
been documented. All patients with a diagnosis of diabetes ophthalmoscopy for evidence of retinal
Diabetic retinopathy is an extremely should have a comprehensive annual eye neovascularizaiton. Optimally, these exams
variable disease. A patient may present examination with dilation. This are performed by eyecare practitioners.
with multiple retinal hemorrhages at one examination should include a slit lamp Optometrists who perform dilated eye
visit and a few months later return with evaluation for neovascularization of the iris examinations can assess the various stages
virtually no signs of diabetic retinopathy. or anterior chamber angle and for cataracts. of diabetic retinopathy. They would need
However, certain signs of diabetic retinop- The dilated fundus evaluation should to refer any patients with potentially sight-
athy will not resolve without treatment. include a magnified lens analysis to check threatening findings to the general

of Diabetes
Legend Color names in parentheses indicate color of the arrow in the corresponding figure.
patient has high-risk PDR and may be a

viable option for patients who are
approaching high-risk PDR or who
have severe NPDR. This procedure
is done with the goal of preventing neo-
vascularization from occurring or
worsening, to induce regression of any
existing neovascularization, and to reduce
the risk of vitreous hemorrhage or trac-
tional retinal detachment.20 It involves
using a laser to make many burns in the
peripheral retina (Figures 4A and 4B).
Focal or grid laser photocoagulation
have been shown to reduce moderate vi-
sion loss in patients with DME by up to
50%.21 Focal laser seals leaking microan-
eurysms, while grid laser is used for more
diffuse macular edema. Photocoagulation
increases local oxygenation by reducing
retinal blood flow, which results in the
Figure 6. Anterior segment image of neovascularization of the iris. Note the fine
decrease of macular edema.22
net of blood vessels surrounding the pupil and extending, especially inferiorly,
Antivascular endothelial growth factor
toward the anterior chamber angle.
(anti-VEGF) drugs are quickly replacing
laser as first-line treatment of DME.23
Anti-VEGF drugs target VEGF, binding
to it and preventing the growth of new,
weak, and permeable blood vessels. Intra-
vitreal injections of anti-VEGF drugs are
indicated when DME is present. Patients
with DME should be treated before
PRP is performed to the rest of the reti-
na due to the risk of macular edema ex-
acerbation after PRP.
Anti-VEGF injections are considered
the standard of care for patients who de-
velop DME and have best corrected vi-
sual acuity worse than 20/32.24 This
treatment combined with focal or grid
photocoagulation results in better visual
outcomes than laser treatment alone. De-
laying the photocoagulation may be ben-
eficial in this course of treatment, as only
50% of eyes require laser treatments after
Figure 7A. Proliferative diabetic retinopathy illustrating neovascularization of the
24 weeks of intravitreal anti-VEGF in-
disc (blue).
jections. Data shows that within 3 to 5
ophthalmologist or retinal specialist. Any tunity to markedly improve the annual years of therapy, there is a 25% chance of
evidence of macular edema or neovascular diabetic retinopathy examination rate in no longer needing injections at all.25
changes of the iris or retina need to be a cost-effective manner.18,19 These same Current anti-VEGF agents include:
referred urgently for ophthalmologic fundus photographs can be used as a pegaptanib (Macugen), ranibizumab (Lu-
assessment and management. platform for educating the patient about centis 0.3 mg), aflibercept (Eylea), and
Remote diagnosis of diabetic retinopa- diabetic retinopathy and potentially im- bevacizumab (Avastin).
thy by the use of telemedicine (retinal prove overall diabetic compliance. Intravitreal injections of triamcinolone
cameras and photographic surveillance) Panretinal photocoagulation (PRP) is a (Kenalog,Triescence) have been shown to
in a primary care setting has the oppor- laser procedure that is performed when a decrease macular thickness and improve
of Diabetes
treatment and risk of complications in patients

with type 2 diabetes (UKPDS 33). UK Prospec-
tive Diabetes Study (UKPDS) Group. Lancet.
1998;352(9131):837-853.
9. Boyer DS, Hopkins JJ, Sorof J, Ehrlich JS. Anti-
vascular endothelial growth factor therapy for dia-
betic macular edema. Ther Adv Endocrinol
Metab. 2013;4(6):151-169.
10. Holdeman NR. Diabetes mellitus. In: Onofrey BE,
Skorin L, Holdeman NR, eds. Ocular Therapeutics
Handbook: A Clinical Manual. 3rd ed. Philadel-
phia, PA: Wolters Kluwer; 2011: 398-410.
11. Grading diabetic retinopathy from stereoscopic
color fundus photographs–an extension of the
modified Airlie House classification. ETDRS re-
port number 10. Early Treatment Diabetic Reti-
nopathy Study Research Group. Ophthalmology.
1991;98(Suppl):786-806.
12. Chisiakov DA. Diabetic retinopathy: pathogenetic
mechanisms and current treatments. Diabetes
Metab Syndr. 2011;5(3):165-172.
13. Yau JWY, Rogers SL, Kawasaki R, et al. Global
prevalence and major risk factors of diabetic reti-
nopathy. Diabetes Care. 2012;35(3):556-564.
14. Progression of retinopathy with intensive versus
conventional treatment in the Diabetes Control
and Complications Trial. Diabetes Control and
Complications Trial Research Group. Ophthalmol-
ogy. 1995;102(4):677-661.
Figure 7B. Fluorescein angiography of the same patient as seen in Figure 7A illustrating 15. American Diabetes Association. Diabetes Statis-
tics. American Diabetes Association Web site.
the hyperfluorescence of leaking blood in the area of neovascularization (yellow). www.diabetes.org. Accessed December 21, 2014.
16. Hudson C. The clinical features and classification
visual acuity in patients experiencing the best interest of the patient to refer to of diabetic retinopathy. Ophthalmic Physiol Opt.
DME. Kenalog contains benzyl alcohol a specialist. Patients with diabetes should 1996;16(Suppl 2):S43-S48.
17. Clinical Insights. American Academy of Ophthal-
as a preservative, while Triescence does have a dilated eye examination at least mology Web site. www.aao.org. Accessed De-
not.21 Repeat injections are needed every once a year. Those with poor glucose cember 27, 2014.
18. Wilson C, Horton M, Cavallerano J, Aiello LM.
3 to 4 months and have undesirable side control or other complicating factors Addition of primary care-based retinal imaging
effects in some patients.These side effects may be advised to have their eyes exam- technology to an existing eye care professional
referral program increased the rate of surveil-
include elevated intraocular pressure, ined more often. ■ lance and treatment of diabetic retinopathy. Dia-
which can lead to glaucoma, as well as betes Care. 2005;28(2):318-322.
19. Whited JD, Datta SK, Aiello LM, et al. A modeled
the accelerated formation of cataracts.27 economic analysis of a digital tele-ophthalmology
Another option for steroid treatment of system as used by three federal health care agen-
cies for detecting proliferative diabetic retinopathy.
DME are the intravitreal implants dexa- Telemed J E Health. 2005;11(6): 641-651.
methasone (Ozurdex) or fluocinolone 20. Heug LZ, Comyn O, Peto T, et al. Diabetic reti-
REFERENCES: nopathy: pathogenesis, clinical grading, manage-
(Iluvien). The beauty of steroid implants ment and future developments. Diabet Med.
1. Prevent Blindness America. 2012 fifth edition of 2013;30(6):640-650.
is that they release low-dose corticoste- vision problems in the US. Vision Problems US 21. Photocoagulation for diabetic macular edema.
roid for as many as 36 months with a Web site. www.visionproblemsus.org. Accessed ETDRS report number 1. Early Treatment Diabet-
December 21, 2014. ic Retinopathy Study Research Group. Arch Oph-
single injection.28 2. National Eye Institute Statement, November thalmol. 1985;103(12):1796-1806.
Vitrectomy is indicated in diabetics 2012. Sharp rise in diabetic eye disease makes 22. Shamsi HN, Masaud JS, Ghazi NG. Diabetic
American Diabetes Month ever more important. macular edema: new promising therapies. World
who have a nonclearing vitreous hemor- National Eye Institute Web site. www.nei.nih.gov/ J Diabetes. 2013;4(6):324-338.
rhage, fibrosis, or traction that threatens news/statements/diabetesmonth2012.asp . 23. Cheung N, Wong IY, Wong TY. Ocular anti-VEGF
Accessed April 2, 2015. therapy for diabetic retinopathy: overview of clini-
the macula. Vitrectomy is an outpatient 3. Centers for Disease Control and Prevention. cal efficacy and evolving applications. Diabetes
surgical procedure in which the vitreous 2011 national diabetes factsheet. Centers for Care. 2014;37(4):900-905.
Disease Control and Prevention Web site. www. 24. Diabetic Retinopathy Clinical Research Network.
gel is removed from the eye. Patients cdc.gov/visionhealth/basic_information/eye_dis- A randomized trial comparing intravitreal triam-
with a vitreous hemorrhage that has not orders.htm. Accessed January 1, 2015. cinolone acetonide and focal/grid photocoagula-
4. Centers for Disease Control and Prevention. Diabe- tion for diabetic macular edema. Ophthalmology.
cleared on its own after 1 to 3 months tes and eye disease. Centers for Disease Control 2008;115(9):1447-1449.
should be referred to a retina specialist and Prevention Web site. www.cdc.gov/visionhealth/ 25. Ho AC, Zhang J, Ehrlich JS. Ranibizumab for di-
data/national.htm. Accessed January 1, 2015. abetic macular edema: long-term open-label ex-
for a vitrectomy.17 5. Zhang X, Saaddine JB, Chou CF, et al. Preva- tension of the Phase III RIDE and RISE trials. In-
lence of diabetic retinopathy in the United States, vest Ophthalmol Vis Sci. 2014;55:1704.
2005-2008. JAMA. 2010;304(6):649-656. 26. Chan WC, Tsai SH, Wu AC, et al. Current treat-
CONCLUSION 6. Klein R. Hyperglycemia and microvascular and ments of diabetic macular edema. Int J Gerontol-
The ability to recognize these signs of macrovascular disease in diabetes. Diabetes ogy. 2011;5:183-188.
Care. 1995;18(2):258-268. 27. Ranchod TM, Fine SL. Primary treatment of dia-
diabetic retinopathy will allow for a more 7. Epidemiology of severe hypoglycemia in the Dia- betic macular edema. Clin Interv Aging.
streamlined referral process when an oph- betes Control and Complications Trial. The 2009;4:101-107.
DCCT Research Group. Am J Med. 28. Iluvien for Diabetic Macular Edema. Almera Sci-
thalmologist is required for appropriate 1991;90(4):450-459. ences Web site. www.alimerasciences.com/prod-
care. If there is uncertainty, it is usually in 8. Intensive blood glucose control with sulphonyl- ucts/iluvien-for-diabetic-macular-edema-dme.
ureas or insulin compared with conventional Accessed December 29, 2014.

COVID Round Up
21 Existing Drugs, Respiratory Droplets

Michael Potts
recently published scientific literature. It includes sections

on renal, hematologic, cardiovascular, gastrointestinal,
hepatobiliary, endocrinologic, neurologic, and dermatologic
manifestations.
21 Existing Drugs4
In a study published in Nature, researchers examined
approximately 12,000 clinical-stage or FDA-approved small
molecules in an effort to find any that could be repurposed
for the treatment of COVID-19. Overall, they identified
100 molecules, including 21 currently existing drugs that
can inhibit the replication of SARS-CoV-2, 13 of which were
shown in previous clinical trials to be effective at doses likely
to be safe for patients with COVID-19. Two of the drugs,
Physics of Respiratory Droplets1,2 astemizole and clofazimine, are already FDA-approved for
In a new study, researchers used collision rate theory the treatment of allergies and leprosy, respectively. Four
to evaluate and predict the spread of respiratory droplets in drugs were shown to work synergistically with remdesivir.
various conditions. They found that these droplets can travel
between 8 and 13 feet depending on the weather, without In-ICU Mortality Rates
accounting for wind, suggesting that without masks, 6 feet A recent analysis found that rates of in-ICU mortality
of social distancing may not be enough. among patients with COVID-19 decreased significantly
“If you’re in a colder, humid climate, droplets from a over the course of the pandemic, from nearly 60% at the
sneeze or cough are going to last longer and spread farther end of March 2020 to roughly 42% at the end of May.
than if you’re in a hot dry climate, where they’ll get evaporated
faster. We incorporated these parameters into our model of REFERENCES:
infection spread; they aren’t included in existing models as far 1. Chaudhuri S, Basu S, Kabi P, et al. Modeling the role of respiratory droplets
as we can tell,” the researchers said in a press release. in Covid-19 type pandemics. Published online June 30, 2020. Phys Fluids.
doi:10.1063/5.0015984
2. New model connects respiratory droplet physics with spread of COVID-19.
COVID-19 Effects Beyond the Lungs3 News release. San Diego, CA: UC San Diego; July 20, 2020. http://jacobss-
A new review published in Nature Medicine details chool.ucsd.edu/news/news_releases/release.sfe?id=3087
the known effects of COVID-19 on organ systems other 3. Gupta A, Madhavan MV, Landry DW, et al. Extrapulmonary manifestations
than the lungs. The review was written by researcher- of COVID-19. Nature Med. 26(7):1017-1032. doi:10.1038/s41591-020-
0968-3
clinicians from Beth Israel Deaconess Medical Center 4. Riva L, yuan S, Chanda SK, et al. Discovery of SARS-CoV-2 antiviral drugs
and Columbia University Irving Medical Center and was through large-scale compound repurposing. Published online July 24,
based upon their own experiences as well as a review of 2020. Nature. doi:10.1038/s41586-020-2577-1
New Data Indicate Remdesivir May Reduce Hospital Stay

Christina Vogt
R
emdesivir appears to be superior to placebo in reducing the New England Journal of Medicine.
time to recovery among adult patients hospitalized “These preliminary findings support the use of
with COVID-19 who require supplemental oxygen remdesivir for patients who are hospitalized with COVID-19
therapy, according to new, preliminary data published in and require supplemental oxygen therapy,” the authors of
COVID Round Up
the study wrote. “However, given high mortality despite the

use of remdesivir, it is clear that treatment with an antiviral
drug alone is not likely to be sufficient,” they noted.
These findings emerged from a double-blind,
randomized, placebo-controlled trial of intravenous
remdesivir among adult patients hospitalized with
COVID-19 with evidence of lower respiratory tract
involvement. Patients (N = 1063) were randomly assigned
to receive one of the following options for up to 10 days:
• A 200-mg loading dose of remdesivir on day 1, followed
by 100 mg remdesivir daily for up to 9 additional days)
• Placebo
The primary outcome was defined as time to recovery
(when patients were either discharged from the hospital or
hospitalized for infection-control purposes only).
Data were collected from 1059 patients who underwent
randomization (538 in the remdesivir group and 521 in
the placebo group). Ultimately, early unblinding of the (21.1%) of the 541 patients who had been randomly
results was recommended because findings indicated that assigned to remdesivir and 141 (27.0%) of the 522 patients
time to recovery had been reduced in the remdesivir group who had been randomly assigned to placebo.
compared with the placebo group. “Future strategies should evaluate antiviral agents
Preliminary results of the trial showed that median in combination with other therapeutic approaches or
recovery time was 11 days in the remdesivir group compared combinations of antiviral agents to continue to improve
with 15 days in the placebo group, with a rate ratio for patient outcomes in COVID-19,” the researchers concluded.
recovery of 1.32. According to Kaplan-Meier estimates, the
rate of mortality by 14 days was 7.1% in the remdesivir REFERENCES:
group compared with 11.9% in the placebo group, with a • Biegel JH, Tomashek KM, Dodd LE, et al; ACTT-1 Study Group Members.
hazard ratio for death of 0.70. Remdesivir for the treatment of Covid-19 — preliminary report. N Eng J
Serious adverse events were reported among 114 Med. Published online May 22, 2020. doi:10.1056/NEJMoa2007764

Legal Pearls
Law Prespecitve In Medicine
The Folly of Ordering, Then Ignoring,

Radiographs
Ann W. Latner, JD
M
rs E, a 58-year-old woman with severe colon inertia, developed an anastomotic
leak after surgery to remove a dead spot on her colon. After several unsuccessful
surgeries, the patient underwent a 17-hour laparotomy. As Dr D was getting
ready to close the incision, the scrub nurses told him that the sponge count was off
and that one was missing. Dr D ordered a radiograph, but before he looked at the
results, he found what he believed to be the sponge and removed it. However, the
radiograph actually showed that 2 sponges had been left inside the patient.
Over the next 2 months, the patient had further surgeries to correct a fistula
which kept opening. Eventually, Dr D looked at the radiograph from the 17-hour
surgery and realized that a sponge still remained in the patient. The physician told
the patient and her husband about the sponge but indicated to them that it wasn’t
causing any problems at this time. A few months later, the patient developed an
infection that Dr D suspected was caused by the sponge.
Two unsuccessful surgeries were conducted to attempt to remove the sponge,
but the patient’s spleen was injured during one of the surgeries and the sponge was
not removed. A year later, after undergoing an unsuccessful bowel transplant, Mrs
E died due to multiple organ failure.
Was Dr D responsible?
(Answer and discussion on next page)
This case involves a very common issue–a clinician orders a test and then
Ann W. Latner, JD, is a freelance writer and attorney based in New York. She was formerly
the director of periodicals at the American Pharmacists Association and editor of Pharmacy
Times.

Legal Pearls
What’s the “Take Home”?

Had Dr D looked at the radiograph before he closed the patient during
the surgery, he would have been able to remove the sponge. Had he looked
at the radiograph results within the first week or 2 after the surgery and
noticed the sponge, he still would have had a good chance of removing it
successfully. But by the time he looked at the radiograph almost 2 months
later, removing it successfully was no longer an option.
Although the jury did not find Dr D actually responsible for the patient’s
death, they found him responsible for unnecessary surgeries and injury
caused by leaving the sponge in the patient’s body.
Dr D could have avoided this by simply looking at the radiograph results
right after ordering them. This is common error that is seen in every type
of medical practice–diagnostic tests or scans are ordered, and then the
results are not looked at, followed up on, or conveyed to the patient.
does not look at the results or looks at them much later, what he believed to be the sponge, removed it, and was
depriving the patient of a complete diagnosis. This particular told by the medical team that the sponge count was now
case involved a surgery, but whether you are a surgeon or a correct. However, it was not. The radiograph, which had
general practitioner, tests that are ordered should always be not been looked at, actually showed that 2 sponges were in
followed up on. the patient, and Dr D only removed one of them.
Over the next 2 months, the patient had further
Clinical scenario surgeries to correct a fistula which kept opening. Eventually,
The patient, Mrs E, was a 58-year-old woman with Dr D looked at the radiograph from the 17-hour surgery
severe colon inertia which medication had not improved. and realized that a sponge still remained in the patient.
Her first surgery, performed by Dr D, was an exploratory The physician told the patient and her husband about the
laparoscopy. The patient had extensive scarring and sponge but indicated to them that it wasn’t causing any
adhesions, as well as a dead spot in the colon. Dr D problems at this time.
removed part of the colon and attached the small intestine A few months later, the patient developed an infection
to the sigmoid colon. After this surgery, Mrs E developed that Dr D suspected was caused by the sponge. Two
an anastomotic leak, resulting in bowel contents leaking unsuccessful surgeries were conducted to attempt to remove
into her abdomen. This resulted in another surgery the the sponge, but the patient’s spleen was injured during one
next month. Each time the physician would attempt to fix of the surgeries and the sponge was not removed.
holes in the bowel, it would break down after surgery and The patient was transferred to another hospital, where
leak bowel contents into the abdomen. Eventually, Dr D she had numerous surgeries over the next year to address
decided to let the patient heal from the infection caused by holes in her intestines, infections in her abdomen, fistulas,
the leakage for 3 months, after which he would try to hook abscesses, and finally a bowel transplant. A week after
up the colon and intestines. the bowel transplant, the patient began bleeding severely
Three months later, the patient underwent a 17-hour and was taken to emergency surgery. At that time, the
laparotomy. As the surgeon was getting ready to close transplanted bowel was removed so that doctors could stop
the incision, the scrub nurses told him that the sponge the bleeding. By the time the bleeding was stopped, the
count was off and that one was missing. Dr D ordered a physicians concluded that the grafted intestine was not
radiograph, but before he looked at the results, he found healthy enough to put back in the patient. Mrs E remained
Legal Pearls
in intensive care following the surgery and died several Mrs E sustained were consistent with other individuals
weeks later due to multiple organ failure. with similar intestinal problems. The expert further
testified that the sponge did not cause Mrs E’s death.
The trial Dr D admitted that he had negligently failed to
After Mrs E’s death, her husband sought counsel discover the sponge, but that her death was not caused by
from a plaintiff’s attorney and sued the original hospital, this error. Instead, he, and the defense’s medical experts
and Dr D. At trial, the plaintiff’s medical expert testified argued that the real cause of Mrs E’s death was her history
that Dr D’s failure to discover and remove the sponge in of complex intestinal issues.
a timely manner caused chronic infections, poor healing, The jury ultimately awarded $200,000 to the plaintiffs.
and ultimately, the patient’s death. When questioned, the jury said that Dr D’s negligence
The physician’s trial defense was that the retained caused injuries to Mrs E, and that the hospital provided
sponge was not the cause of Mrs E’s death. The defense negligent care, but the jury stopped short of finding that
medical expert testified that there was no indication that Dr D or the original hospital were the proximate cause of
the sponge was infected, and that the complications that Mrs E’s death.
BOTTOM LINE—It is essential to always look at the results of tests you ordered.
Overlooking test results can cause tragic outcomes for both patient and physician.

Spot The Diagnosis
Test Your Diagnostic Skills In Dermatology
Quiz # 34
For 1 week, a 28-year-old man has had this tender, spreading rash on his chin.
He is otherwise healthy.
What does this look like to you?
A. Streptococcal impetigo.
B. Staphylococcal impetigo.
C. Candida folliculitis.
D. Acne.
E. Rosacea
F. Contact dermatitis. .
See answer and discussion on page No 42

Q&A
An Interaction With Experts
How Important is Glucagon in the

Pathophysiology of Diabetes?
Kim A. Carmichael, MD, FACP—Series Editor, is an associate professor of medicine, department of internal medicine, division of
endocrinology, diabetes, and lipid research at Washington University School of Medicine in St. Louis, MO.
Q:
What is glucagon and how does it impact glucose metabolism? levels. After dipeptidyl peptidase-4 (DPP-4) inhibitors (eg,
Glucagon is a hormone, produced by the alpha cell of the sitagliptin, alogliptin, linagliptin) block the enzyme that degrades
pancreas, which increases blood glucose by stimulating endogenous GLP-1, local concentration is increased.8 Exogenous
hepatic glycogenolysis, glucone ogenesis, and inhibiting insulin- GLP-1 agonist analogs (eg, exenatide, liraglutide, albiglutide)
stimulated glycogen synthesis.1,2 In contrast to individuals provide an even greater, more sustained GLP-1 effect.
without diabetes, glucagon increases in response to oral glucose
Q:
in patients with both type 1 and type 2 diabetes.3,4 Glucagon has What role does glucagon have in type 1 diabetes?
negligible effects on muscle glucose disposal.1,5 Oral glucose intake also increases glucagon in persons
Glucagon also is important in the counterregulatory with type 1 diabetes,3 which causes postprandial
response to hypoglycemia by way of its potent stimulation of hyperglycemia. However, these results are independent of
hepatic glucose production.1,6 GLP-1 as levels of this hormone remain unchanged. DPP-4
inhibitors and GLP-1 agonists are not currently approved for
Q:
What affects glucagon secretion in type 2 diabetes and use in type 1 diabetics, but many studies are ongoing to assess
why is this important? their clinical applicability.
Oral glucose (carbohydrate) ingestion stimulates Glucagon secretion also contributes greatly to
production of glucagon-like peptide-1 (GLP-1), a protein hyperglycemia, ketosis, and acidosis in the setting of diabetic
which increases insulin and inhibits glucagon secretion, delays ketoacidosis.1
gastric emptying, and directly stimulates hepatic glucose
Q:
uptake.5 Deficiency of GLP-1, both in secretion and potency of How can glucagon therapy benefit patients with diabetes?
effect7 is the major factor responsible for increased postprandial Because of potent effects on glycogenolysis and
glucagon secretion, which contributes substantially to higher gluconeogenesis, exogenous glucagon may be used
glucose levels in patients with type 2 diabetes.4 by diabetes patients to rapidly treat hypoglycemia. Persons
High intra-islet cell insulin normally suppresses basal prone to hypoglycemia should carry an emergency glucagon
glucagon secretion1 but persons with low beta-cell function, rescue device at all times (Glucagon Emergency Rescue Kit or
and low intra-islet cell insulin, may have relative basal GlucaGen HypoKit).
hyperglucagonemia. Insulin-induced hypoglycemia causes
increased alpha cell glucagon production by way of direct REFERENCE:
sympathetic and parasympathetic autonomic stimulation and 1. Taborsky GJ Jr. The physiology of glucagon. J Dibetes Sci Technol.
circulating epinephrine.1 This protective feedback mechanism 2010;(6):1338-1344.
2. Dineen S, Alzaid A, Turk D, Rizza R. Failure of glucagon suppression contributes
is largely related to neural mechanisms in the brain and can to postprandial hyperglycemia in IDDM. Diabetologia. 1995;38(3):337-343.
be inhibited by repeated hypoglycemia causing the syndrome 3. Hare KJ, Vilsboll T, Holst JJ, Knop FK. Inappropriate glucagon response
after oral compared with isoglycemic intravenous glucose administra-
of hypoglycemiaassociated autonomic failure.1,6 When intra- tion in patients with type 1 diabetes. Am J Physiol Endocrinol Metab.
islet insulin is fully absent, such as in type 1 or advanced type 2010;298(4):E832-E837.
2 diabetes, there is a loss of the compensatory rise in glucagon 4. Shah P, Vella A, Basu A, et al. Lack of suppression of glucagon contributes
to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J
secretion in response to hypoglycemia, thereby placing these Clin Endocrinol Metab. 2000;85(11):4053-4059.
individuals at much greater risk for serious hypoglycemia. 5. Edgerton DS, Cherrington AD. Glucagon as a critical factor in the pathology
of diabetes. Diabetes. 2011;60(2):377-380.
Q:
6. Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure in di-
How do newer diabetes medications affect glucagon in abetes. NJEM. 2013;369(4):362-372.
type 2 diabetes? 7. Knop FK, Vilsbol T, Hojberg PV, et al. Reduced incretin effect in type 2 diabetes:
cause or consequence of the diabetic state? Diabetes. 207;56(8):1951-1959.
Several medications for diabetes now target the 8. Freeman JS. Role of the incretin pathway in the pathogenesis of type 2
bioavailability of GLP-1, which lowers postprandial glucose diabetes mellitus. Cleve Clin J Med. 2009;76(Suppl 5):S12-S19.

X-Ray Tutorial
The Key To Interpreting X-Ray
Case 10 Clinical history

A 40 year old male presents to ED with shortness of breath and a 6 week history of cough. He has a history of testicular cancer,
which was treated with surgery. He is a non-smoker. On examination, he has saturations of 100% in air and is afebrile. Lungs
are resonant throughout with good bilateral air entry. A chest X-ray is requested to assess for possible malignancy.
Intrepretation on the next page...

X-Ray Tutorial
Case 10
X-ray Report
Patient ID: Anonymous Normal pulmonary vascularity. No pneumoperitoneum.
Projection: PA
Penetration: Adequate – vertebral CIRCULATION The imaged skeleton is intact with no
bodies just visible behind heart The heart is not enlarged. fractures or destructive bony lesions
Inspiration: Adequate – 8 anterior ribs visible.
visible The heart borders are clear. A mass is
Rotation: Not rotated projected over the right heart border, The visible soft tissues are
although the border remains visible. unremarkable.
AIRWAY
The trachea is central. The aorta appears normal. Extras + Review Areas
No vascular lines, tubes, or surgical
BREATHING The mediastinum is central, not clips.
There is a small, lobulated mass widened, with clear borders.
medially in the right lower zone. It is Lung Apices: Normal
partially projected over the right heart Normal size, shape, and position of Hila: Normal
border. The lungs are otherwise clear. both hila. Behind Heart: Mass projected over the
right heart border
The lungs are not hyperinflated. DIAPHRAGM + DELICATES Costophrenic Angles: Normal
Normal appearance and position of Below the Diaphragm: Normal
The pleural spaces are clear. the hemidiaphragms.
Central trachea
Clear left lung
Clear right heart border
Clear left heart border Enlarged version
Right lower zone mass
Normal left
hemidiaphragm
Normal right
hemidiaphragm
Diagnosis – Retrocardiac Mass

Summary, Investigations and Management
This X-ray demonstrates a small rounded mass medially in the right performed to identify any underlying malignancy.
lower zone. The mass is projected over the right cardiac border,
The patient should be referred to oncology services for further
which remains visible, indicating the mass is not in the middle lobe
management, which may include biopsy and MDT discussion.
or anterior mediastinum. Given the history of previous malignancy,
Treatment, which may include surgery, radiotherapy, chemotherapy,
this is suspicious for a metastasis.
or palliative treatment, will depend on the outcome of the MDT
Initial blood tests may include FBC, U/Es, LFTs, & bone profile. discussion, investigations, and the patient’s wishes.
A staging CT chest, abdomen and pelvis with IV contrast should be

Annotations Highlighting the Major X-ray Findings
Central trachea
Clear left lung
Clear right heart border
Clear left heart border
Right lower zone mass
Normal left
hemidiaphragm
Case 10
X-Ray Tutorial
Vol 11 No 4, July, 2020

Normal right
hemidiaphragm
GP Clinics
29
FDA Alerts
Be The First To Know To Practice
FDA Expands
Strengthens
UseClozapine
for Antibiotic
Con-
stipation Warning
Colleen Murphy
T
Michael Potts
he US Food and Drug Administration (FDA) has
FDA Approves New Option for approved a combination of imipenem-cilasta-
tin and relebactam (Recarbrio) for the treatment
Heavy Menstrual Bleeding of patients aged 18 or older with hospital-acquired
bacterial pneumonia or ventilator-associated bacterial
Michael Potts pneumonia (HABP/VABP).
The therapy had already been FDA-approved
T
for the treatment of patients with complicated urinary
he FDA has approved Oriahnn (estrogen and
tract infections and complicated intraabdominal
progestin combination consisting of elagolix,
infections who have limited or no alternative
estradiol and norethindrone acetate) for the
treatment options.
treatment of heavy menstrual bleeding associated
The new approval comes after the imipenem-
with uterine leiomyomas (fibroids) in premenopausal
cilastatin and relebactam combination was shown
women.
to be safe and effective in a randomized, controlled
The efficacy of the treatment was examined in
clinical trial that comprised 535 hospitalized adults
2 clinical trials with a total of 591 premenopausal
with HABP/VABP due to gram-negative bacteria.
women with heavy menstrual bleeding, defined as
The most common adverse reactions among
at least 2 menstrual cycles with greater than 80 mL
patients treated with the imipenem-cilastatin and
of menstrual blood loss. The women were assigned
relebactam combination for HABP/VABP—which
to either Oriahnn or placebo for 6 months. In the
is administered intravenously—were increased
first study, 68.7% of those who received the new
aspartate/alanine aminotransferases, anemia,
treatment option achieved the endpoint of 50% or
diarrhea, hypokalemia, and hyponatremia.
greater reduction in blood loss compared with base-
“As a public health agency, the FDA addresses
line during the final month, compared with 8.7% of
the threat of antimicrobial-resistant infections by
those in the placebo group. In the second study,
facilitating the development of safe and effective
76.5% of patients receiving Oriahnn achieved the
new treatments,” Sumathi Nambiar, MD, MPH,
endpoint, compared with 10.5% of the placebo
director of the Division of Anti-Infectives within the
group patients.
Office of Infectious Disease in FDA’s Center for Drug
Oriahnn may cause bone loss over time and
Evaluation and Research, said in the FDA press
should not be taken for more than 24 months. The
release. “These efforts provide more options to fight
most common adverse effects were hot flushes,
serious bacterial infections and get new, safe and
headache, fatigue, and irregular vaginal bleeding.
effective therapies to patients as soon as possible.”
It includes a boxed warning on the risk of vascular
events and thrombotic or thromboembolic disorders. REFERENCE:
REFERENCE: FDA approves antibiotic to treat hospital-acquired bacterial pneumonia

and ventilator-associated bacterial pneumonia. News release. US Food
FDA Approves New Option to Treat Heavy Menstrual Bleeding and Drug Administration. June 4, 2020. Accessed June 5, 2020.
Associated with Fibroids in Women. News release. US Food and Drug https://www.fda.gov/news-events/press-announcements/fda-approves-
Administration. May 29, 2020. https://www.fda.gov/news-events/ antibiotic-treat-hospital-acquired-bacterial-pneumonia-and-ventilator-
press-announcements/fda-approves-new-option-treat-heavy-menstrual- associated
bleeding-associated-fibroids-women.

Whats Take The Home
Clinical Evidence From Doctors’ Clinic
A Family with a Variety of

“Flu” Symptoms
Ronald Rubin, MD—Series Editor
A
34-year-old female patient requests an office visit after experiencing flu-like symptons for the last few days. She
was never febrile but had a sore throat along with nasal congestion. She is asking for an antibiotic to hasten the
resolution of her illness. She is accompanied by her 3-year-old son and is also requesting an antibiotic for him. He,
too, had been ill, but with a fever and left ear pain for the last 2 days. He is currently afebrile but otoscopy demonstrates
a dull, tympanic membrane with a middle ear effusion (MEE).
WHICH OF THE FOLLOWING IS THE MOST ACCURATE ADVICE

FOR THIS SITUATION?
A. The risk of antibiotic-related diarrhea outweighs any benefit from an antibiotic
for the child.
B. Antibiotics may resolve his symptoms but will have no effect on his hearing.
C. Appropriate antibiotic treatment can effectively reduce his MEE and concomitant
hearing impairment.
D. Any beneficial effects from antibiotics will be short-lived, with no benefits compared to
no antibiotics after the first 2 weeks.
and public health issues as well as antibiot- Diagnosis required either acute symp-
Correct Answer: C ic-related diarrhea, a frequent side effect.1 toms of respiratory infection and/or
However, 2 recent well-done studies have ear-related symptoms and signs of tym-
How to approach children’s middle ear demonstrated significant, meaningful ben- panic membrane inflammation together
infections has long been the subject of efits accruing to properly chosen pa- with MEE detected in pneumatic otos-
discussion and controversy since the ad- tients.2,3 In the most recent of these,2 a copy. Thus, there was no dilution of an-
vent of antibiotics. On the positive side placebo-controlled study was performed tibiotic effect due to treating large num-
for antibiotic usage, is the shortening of in 84 young people, half of whom re- ber of “colds” which would not benefit
symptoms (especially pain) and duration ceived typical and appropriate antibiotics from antibiotics.
of illness in these young patients. On the (amoxicillin with or without clavulanic When analyzed, this study demon-
negative side, however, is the perceived acid), while the other half received place- strated that indeed there was the
overuse of antibiotics with its resistance bo. Of importance was patient selection. expected 1-day (3.2-2.2) improvement

Whats Take The Home
A Family with a Variety of “Flu” Symptoms
TAKE-HOME MESSAGE
Despite a background of controversy with waxing and waning enthusiasm for the use
of antibiotics in pediatric acute otitis media (AOM), most recent data suggests that
appropriate and accurate diagnosis of AOM provides notable benefit to antibiotics—not
just in duration of illness, but also in rate and extent of resolution of illness in middle
ear effusion and tympanometry, with potential for less hearing impairment. There is a
12% diarrhea rate associated with this strategy, which is usually mild and self-limited.
in disappearance of earache in the who did not have acute otitis and thus 1-week prescription for amoxicillin- cla-
antibiotic group. Further, and more would not and could not benefit from vulanate was provided for the child.
importantly, there was meaningful and antibiotics (yet were just as likely to get Within 2 days all of his symptoms had
significant improvement and resolution antibiotic-related diarrhea!). Therefore, resolved, he was well and back at daycare.
times in the primary outcome parame- these factors would dilute and mask any A follow-up exam 10 days later re-
ters of resolution in MEE—2 weeks beneficial effect of antibiotics. 2. An vealed resolution of the MEE and a
sooner (P=0.02); as well as significantly accompanying editorial stresses that normal tympanic membrane. He never
quicker time to normal ear otoscopy. benefits of antibiotics rely on accurate developed diarrhea. n
These benefits continued past 2 months diagnosis of acute otitis rather than in-
out from diagnosis. Since MEE is discriminant use for a variety of less Ronald Rubin, MD, is a professor of
known to impair hearing with its at- specific complaints and situations.1 medicine at Temple University School of
tendant problems with language and A ma j o r d i f f i cu l t y a s s o ci a t ed Medicine and chief of clinical hematology in
learning, one can postulate very impor- with antibiotic usage is antibiotic- the department of medicine at Temple Uni-
tant positive effects accruing to the an- associated diarrhea as mentioned in versity Hospital, both in Philadelphia, PA.
tibiotic related rapidity and depth of Answer A. This toxicity can be ex-
resolution.2 Thus Answer B, that anti- pected in about 10% of treated cases.2,3 REFERENCES:
biotics induce symptom relief but will Although indeed troublesome, the 1. Tapiainen T, Kujala T, Renko M, et al.
have no effect on hearing, is incorrect. diarrhea is rarely severe and usually Effect of antimicrobial treatment of
Further, Answer D, that antibiotics’ net resolves within 3 days of cessation of acute otitis media on the daily disap-
positive effects for symptom relief and antibiotics. 1 The low incidence and pearance of middle ear effusion: a
otherwise, are short-lived, is incorrect. mild severity of this adverse effect placebo-controlled trial. JAMA Pedi-
A key issue when evaluating antibiot- seems quite acceptable in the face of a atr. 2014;168:635-642
ics in acute otitis media in general, and shorter duration of illness across the
2. Pichichero ME. Antibiotics for Acute
the results of this study in particular, is larger group of treated patients and
Otitis Media. Yes or No. JAMA.
accuracy of diagnosis. The authors the documented anatomical benefit in
insisted on firm exam criteria—dem- 2015;313:294-295
the middle ear and functional benefit
onstration of MEE and abnormal otos- in hearing. Therefore, Answer A is 3. Tahntinen PA, Laine MK, Huovinen
copy—to accrue their study groups. incorrect. P, et al. A placebo-controlled trial of
Many previous studies had far less strin- antimicrobial treatment for acute oti-
gent criteria, likely resulting in the in- PATIENT FOLLOW-UP tis media. N Engl J Med.
clusion of large numbers of children Based on the clinical findings, a 2011;364:116-126

Nutritional Pearls
Nutrition and Health
Vitamin D Supplements Don't Prevent

Cancer or Heart Disease
Timothy S. Harlan, MD
A
52-year-old man who isn’t getting enough vitamin D. He tells you that
because of a fear of skin cancer, he tries to avoid unprotected exposure to
sunlight and that he struggles to find foods that are high in vitamin D.
Because of this, he is interested in beginning to take a vitamin D supplement to
help lower his risk of cancer and heart disease.
How do you advise your patient?

(Answer and discussion as under)
Answer
Taking vitamin D supplements does not appear to help prevent cancer and
heart disease. If possible, patients should favor getting vitamin D from
sunlight and food sources over supplementation.
Discussion
For years people have been taking vitamin D supplements in conjunction with
calcium supplements as a way to prevent bone loss. More recently some research has
shown higher incidences of cancer and heart disease in people whose blood levels of
vitamin D were considered low. This is quite serious, as many, if not most people
don't get enough vitamin D. Few foods provide vitamin D in significant amounts,
and for most people their primary source of vitamin D is sunlight. Yet with a greater
Timothy S. Harlan, MD, is a board-certified internist and professional chef who translates the
Mediterranean diet for the American kitchen with familiar, healthy recipes. He is an assistant
dean for clinical services, executive director of The Goldring Center for Culinary Medicine, as-
sociate professor of medicine at Tulane University in New Orleans, faculty chair of the all-new
Certified Culinary Medicine Specialist program, and co-chair of Cardiometabolic Risk Summit.

Nutritional Pearls
Vitamin D Supplements Don't Prevent Cancer or Heart Disease
awareness of the risk of skin cancer, people are avoiding the • Vitamin D supplement and placebo
sun and wearing sunscreen more often, leaving them at higher • Placebo and omega-3 supplement
risk of vitamin D deficiency. • Placebo and placebo
That said, seeing a relationship between low vitamin D For an average of 5 years, the participants were provided
levels and cancer or low vitamin D levels and heart disease is their assigned supplements on a monthly basis. On a yearly
not the same as establishing that low vitamin D causes cancer basis, the participants updated their health information and
or heart disease: the only way to establish that is a randomized, when a participant reported a relevant health-related issue
controlled trial. such as a heart attack, stroke, or cancer diagnosis, the authors
The Research. Funded by grants from the National requested access to their relevant medical records to verify the
Institutes of Health and other organizations, a team of Harvard- diagnosis.
affiliated researchers designed the Vitamin D and Omega-3 Trial The Results. At the close of the study, the authors looked
(VITAL) to assess whether taking oral supplements of vitamin at how many participants of each of the groups experienced a
K or omega-3 fatty acids would prevent cancers or heart disease. heart attack, stroke, death from other heart-related causes, or
They recruited over 25,000 men and women, in the Trial, invasive cancer of any kind. Overall, the rates of heart disease-
who were at least 50 years of age (55 for women). They made related illnesses or cancer did not significantly differ among
sure to recruit an ethnically diverse population that included those assigned to receive either a vitamin D supplement or
at least 5000 black participants, as they are particularly prone a placebo replacement. This was regardless of whether the
to lower levels of vitamin D. The participants had no history participants received omega-3 supplements.
of cancer (other than skin cancer) or heart disease and agreed In an effort to tease out any clinically significant
to limit their intake of vitamin D supplements to less than outcomes, the authors broke out the participants by various
800 IU per day. characteristics, including gender, race, body mass index
At the start of the study, the participants responded to (BMI), and baseline vitamin D levels. While the baseline level
a demographic and health history questionnaire as well as of vitamin D didn't seem to have an effect on outcomes, it
a dietary questionnaire. About 2/3 of the participants also did seem that vitamin D supplementation reduced the risk
underwent blood tests that included an assessment of their of invasive cancers for black participants by about 23%. The
baseline vitamin D levels. Of those, 12.7% had levels that risk of heart disease, however, was not affected to a degree the
would be considered inadequate. authors considered clinically significant (less than 10%).
The authors randomly assigned the participants to 1 of
4 groups: Reference:
• Vitamin D supplement (2000 IU/day) and omega-3 • Manson JE, Cook NR, Lee I, et al. Vitamin D supplements and prevention
supplement (1 gram/day) of cancer and cardiovascular disease. N Engl J Med. 2019;380(1):33-44.
What’s the “Take Home”?

It's important to remember that what the authors were investigating was
the use of supplements and not an increased intake of vitamin D from
food sources. What this study means is that taking vitamin D supplements
to prevent heart disease or cancer is largely pointless unless you are black,
in which case it may be helpful in preventing invasive cancers.
We know from other research that vitamin and antioxidant supplements
may in fact be harmful, while adequate intake of the same substances
from food is helpful. This may also be true with vitamin D; we don't yet
know. So make sure you're getting enough vitamin D by getting out in the
sun (just a few minutes a day is enough, and sunlight through a window
doesn't count) or look for foods that have been fortified with vitamin D
(these commonly include orange juice, breakfast cereals, and milk).
What’sYour Diagnosis?®
Sharpen Your Physical Diagnostic Skills
Multiple Cutaneous Nodules in a

Previously Healthy Male
Alix Mitchell, MD, and David Effron, MD—Series Editor
A
42-year-old male presented to the emergency department
with multiple complaints that had developed over the past
month. He first noticed a painful mass on his left shoulder,
and then more tender lumps began appearing on his abdomen,
back, and neck. He had also been experiencing sharp abdominal,
back, neck, hip, and extremity pains that subsequently forced him
to quit his weekly recreational basketball games. He reported mul-
tiple positives in his review of systems, including night sweats, in-
termittent diarrhea and constipation, nausea and vomiting, and a
weight loss of 20 lbs (≅ 9 kgs).
Figure 1. Image of multiple skin nodules.
HISTORY
The patient had been in an outpatient clinic earlier that
month with similar complaints, including back pain, weight
loss, and skin lesions. At the time, basic labs and lumbar spine
x-rays were performed, all of which were unremarkable. He
was referred to general surgery for biopsy of the skin lesions,
but he came to the emergency department prior to this sched-
uled appointment.
The patient had no significant past medical history. He
takes NSAIDs for his back pain with minimal relief. He is a
half-pack per day smoker but denied any drug or significant A B
alcohol use.
Figures 2a and 2b. Chest x-ray demonstrating small right effusion and
multiple pleural-based densities.
PHYSICAL EXAMINATION
On examination, the patient was in no acute distress, and his
vital signs were normal. He had no scleral icterus. Mucous
membranes were moist. Lungs were clear, and cardiovascular
exam was normal. No neurologic deficits were identified. He
had diffuse abdominal tenderness without guarding or re-
bound.The patient’s skin exam was notable for nodules ranging
from pea to golf ball in size on his posterior neck, supraclavicu-
lar region, and bilateral flanks.These nodules were firm, mobile,
and tender. There was no erythema or fluctuance (Figure 1).
LABORATORY TESTS
The patient received morphine to alleviate pain while tests Figure 3. CT showing pleural based masses.
were conducted. Complete blood count was only remarkable abnormal CXR findings. The scan revealed multiple masses
for slight leukopenia. Liver tests revealed elevated bilirubin, a and adenopathy throughout the chest, abdomen, and pelvis,
slight elevation in his alkaline phosphatase, and a mild transa- pancreatic obstruction, severe compression of multiple vascular
minitis. A basic metabolic panel was normal. structures, and multiple pleural-based masses as identified on
A chest x-ray (CXR) demonstrated multiple pleural-based the CXR (Figure 3).
densities in the right lower chest, the retrocardiac region of
the left lung base, and a small right pleural effusion (Figures What's Your Diagnosis?
2a and 2b). A chest, abdomen, and pelvis scan was performed A. Skin abscesses B. Lipomas C. Skin metastasis
to further evaluate his abdominal complaints as well as the
What’sYour Diagnosis?
Multiple Cutaneous Nodules in a Previously Healthy Male
bone marrow, kidney, and GI malignan-

Answer: Skin metastasis cies.2 Testicular cancer has been found to
be the primary cancer for only 0.5% of
metastatic skin nodules identified
at only 1 cancer center. 2 Most
cutaneous metastases present as solitary
nodules although melanoma and
carcinoma of unknown origin were
found to present with multiple
nodules.1 Skin lesions offer an accessible
biopsy site for diagnostic and therapeu-
tic purposes.
OUTCOME OF THE CASE

The patient was discharged 8 days
later with a plan to initiate chemother-
apy upon review of his case by the on-
Figure 4. Ultrasound guided biopsy of a right flank mass. cology tumor board. At follow-up, an
elevated serum human chorionic go-
nadotropin level was discovered. Al-
though the patient had no palpable
testicular abnormalities, an ultrasound
showed multiple masses (Figure 5).
His chemotherapy was adjusted to tar-
get metastatic germ cell carcinoma of
the testes.
The patient initially had very good
response to chemo and radiation thera-
py, but he relapsed 9 months later. He is
now undergoing salvage therapy to slow
the progression of his disease. ■
Figure 5. Ultrasound demonstrating heterogeneous masses in the testes. Alix Mitchell, MD, is assistant profes-
sor of emergency medicine at Case Western
The patient was informed of the con- ease process. The differential depends Reserve University and an attending physi-
cern for metastatic disease. He was ad- on features of the masses, time course of cian in the department of emergency medicine
mitted for pain control, further evalua- development, as well as patient symptoms. at the MetroHealth Medical Center in
tion, and management. An ultrasound- Benign skin tumors can typically be iden- Cleveland, OH.
guided biopsy of the nodule on his right tified based on their distinctive appear-
flank was performed (Figure 4). The ance. Lipomas present as soft masses that David Effron, MD, is assistant profes-
oncology service evaluated the patient gradually increase in size. Abscesses pro- sor of emergency medicine at Case Western
and diagnosed a poorly differentiated duce fluctuance, tenderness, and erythe- Reserve University, attending physician in
non-small cell cancer with neuroendo- ma. Systemic infections can produce skin the department of emergency medicine at the
crine features and unknown primary lesions, and careful evaluation of the le- MetroHealth Medical Center, and consultant
source. An endoscopic retrograde cholan- sions as well as travel and exposure history emergency physician at the Cleveland Clinic
giopancreatography with stent place- can help to confirm these diagnoses. Skin Foundation, all in Cleveland, OH.
ment relieved his biliary obstruction. A lesions that do not present with charac-
single treatment of radiation therapy was teristic features should prompt consider- REFERENCES:
directed at a painful metastatic lesion on ation for a biopsy for further evaluation. 1. Marcoval J, Moreno A, Peyrí J. Cutaneous
his right proximal humerus. Skin metastasis may develop in nearly infiltration by cancer. J Am Acad Derma-
10% of patients with cancer; it is a rare tol. 2007;57(4):577-580.
2. Wong CY, Helm MA, Helm TN, Zeitouni N.
DISCUSSION presentation of internal cancers.1 Cancers
Patterns of skin metastases: a review of 25
Skin nodules can originate locally in most likely to develop skin nodules are years’ experience at a single cancer cen-
the skin or as a sign of a systemic dis- breast, lung, skin, lymph node, blood and ter. Int J Dermatol. 2014;53(1):56-60.

Image Diagnosis
Self – Test Your Diagnostic Acumen
Disappearing Digits: Metabolic Bone

Disease in End-Stage Renal Disease
Shitij Arora, MD, FACP1; Fathima Jahufar, MD2
1
Department of Internal Medicine and Division of Hospital Medicine, Albert Einstein College of Medicine, Bronx, NY.
2
Department of Internal Medicine, Montefiore Hospital and Medical Center, Bronx, NY.
CASE PRESENTATION
A 32-year-old man with end-
stage renal disease on hemodialysis
since 2009 presented with reports of a
“disappearing finger nail.” He denied
bone pain and muscle weakness but
confirmed dry skin and pruritus.
He was noncompliant with his
prescribed cinacalcet and sevelamer.
On examination, he was noted to have
loss of lunula in the left index finger
with shortening of the distal phalanx
(Figure 1). Laboratory test results Figure 1 – Gross appearance of the left hand Figure 2 – Plain radiograph of the left hand
showed a phosphorus level of 7.0 mg/ showing shortened finger length and loss of showing near complete osteolysis of the
dL and an intact parathyroid (PTH) lunula in the left index finger. distal phalanx of the index finger and similar
changes involving nearly all bones of the hand.
level of 2380 pg/mL. Radiographic to the development of metabolic bone
imaging of his hands showed severe disease.1,2 Current treatment options is greater than 1 cm, may be resistant to
generalized bone resorption (the include correcting vitamin D deficiency, medical treatment.4 There is a paucity of
left hand is shown in Figure 2). His controlling dietary phosphorus intake, clinical trials comparing medical therapy
PTH scan showed retention of Tc- and prescribing phosphate binders and with surgical parathyroidectomy in this
99m methoxyisobutylisonitrile in the calcimimetics (cinacalcet). Recommen- patient population.
left lower pole and right upper pole, dations include use of non-calcium- Cruzado et al5 studied the
which was discordant with Tc-99m containing phosphate binders such as effect of cinacalcet and compared
pertechnetate uptake. The scan findings lanthanum and sevelamer. it with parathyroidectomy in renal
were consistent with nodular PTH The Kidney Disease Improving transplant patients with a glomerular
hyperplasia, and he was referred for Global Outcomes guidelines filtration rate greater than 30 mL/
parathyroidectomy. recommend parathyroidectomy in kg/min. Parathyroidectomy led to a
patients with stage G5D with severe statistically significant reduction in
DISCUSSION hyperparathyroidism who fail to respond PTH levels starting at 3 months and
Metabolic bone disease is a to medical or pharmacological therapy the effect was even more pronounced
common complication in chronic (grade 2B). Historically, a PTH level at 12 months.5
kidney disease. In the past decade, a greater than 800 pg/mL despite medical
number of mechanisms for unchecked treatment would lead to a referral for References:
PTH level elevations have been parathyroidectomy (>9 × the upper 1. Su N, Du X, Chen L. FGF signaling: Its role
identified. Low vitamin D levels, limit of a normal assay).3 There are data in bone development and human skeleton
resistance of PTH-sensing receptors, to suggest that hyperparathyroidism diseases. Front Biosci 2008;13:2842-65. DOI:
https://doi.org/10-2741/2890.
and dysregulation of the fibroblast caused by nodular hyperplasia, along
2. Felsenfeld A, Silver J. Pathophysiology and
growth factor 23PTH axis can all lead with cases where the ultrasonography of clinical manifestations of renal osteodystrophy.
to prolonged excessive synthesis and the PTH glands shows volume greater In: Olgaard K, editor. Clinical guide to bone and
secretion of PTH, eventually leading than 500 mm3 or the largest diameter Contd... page 42

Drugs In Practice
Critical Review of Drugs Used in Daily Practice
This column carries evidence-based, peer-reviewed evaluations of new FDA-approved drugs with conclusions reached by a
consensus of experts, and new information on previously approved drugs including pivotal clinical trials, new indications, and
safety warnings. Also, will carry, from time to time, the comparative reviews of drugs for a given indication with particular
attention to clinical efficacy, adverse effects and drug interactions.

H
ealthcare providers are often asked if drugs can be used Services advised that it would be reasonable if necessary to use
past their expiration date. Because of legal restrictions and the antiviral products Tamiflu (oseltamivir; 75-mg capsules)
liability concerns, manufacturers do not sanction such and Relenza (zanamivir inhalation powder) for up to 15 and
use and usually do not comment on the safety or effectiveness 10 years, respectively, after their date of manufacture if the
of their products beyond the date on the label. Since our last products were stored under labeled conditions.5
article on this subject,1 more data have become available.
HEAT, HUMIDITY, AND LONG-TERM STORAGE
SAFETY Storage in high heat and/or humidity can accelerate
There are no published reports of human toxicity due the degradation of some drug formulations, but in one
to ingestion, injection, or topical application of a currently study, captopril tablets, theophylline tablets, and cefoxitin
available drug formulation after its expiration date. Renal sodium powder for injection, stored at 40°C and 75%
tubular damage has been reported with use of degraded relative humidity, remained stable for 1.5-9 years beyond
tetracycline in a formulation that is no longer manufactured.2 their expiration dates.6 In another study, theophylline tablets
retained 90% of their labeled content 30 years past their
THE EXPIRATION DATE expiration date.7 A study of 8 products that had been stored
The manufacturer’s expiration date is based on the in their unopened original containers for 28-40 years past
stability of the drug in the original sealed container. The their expiration dates found that 12 of 14 active ingredients
date does not necessarily mean that the drug was found to had retained ≥90% of their original potency; aspirin retained
be unstable after a longer period; it only means that real- <5% of its potency, and amphetamine <60%.8
time data or extrapolations from accelerated degradation
studies indicate that the drug is expected to be stable on that LIQUID FORMULATIONS
date if stored in the closed container under recommended Solutions and suspensions are generally less stable than
conditions. Most drug products have a labeled shelf life of solid dosage forms, but in one report, 4 outdated samples
1-5 years, but in some cases (e.g., ophthalmic products), the of atropine solution (three up to 12 years past expiration
expiration date on the original container no longer applies and one >50 years past the expiration date) were all found
once it is opened. to contain significant amounts of the drug.9 Drugs in
solution that have become cloudy or discolored or show
STABILITY signs of precipitation should not be used. Suspensions are
Data from the US Department of Defense/FDA Shelf particularly susceptible to freezing. Limiting factors with
Life Extension Program, which tests the stability of drug ophthalmic drugs include evaporation of the solvent and
products past their expiration date, have shown that 2650 a decreasing ability of preservatives to inhibit microbial
of 3005 lots (88%) of 122 different products stored in growth.10
their unopened original containers were able to have their
shelf lives extended by an average of 66 months past the EPINEPHRINE
labeled expiration date.3 Potassium iodide, which has been Epinephrine solutions, which can reverse the life-
extensively stockpiled for use in a radiation emergency, has threatening effects of allergic reactions, may lose potency
shown no significant degradation over many years.4 A 2020 after the expiration date. In a study of 34 auto-injectors that
report from the US Department of Health and Human had expired within the previous 90 months, the decrease
Drugs In Practice
in epinephrine content was inversely proportional to the no published reports of toxicity from degradation products
number of months past the expiration date.11 Multiple of currently available drugs.
studies of epinephrine auto-injectors (including EpiPen,
EpiPen Jr, Auvi-Q, and the generic for Adrenaclick) have References:
found pens up to 6 years past their expiration dates to 1. Drugs past their expiration date. Med Lett Drugs Ther 2015;57:164.
contain ≥80% of the labeled dose,12-14 but these studies 2. GW Frimpter et al. Reversible “Faconi syndrome” caused by degraded
tetracycline. JAMA 1963;184:111.
were not designed to detect the potential conversion of 3. RC Lyon et al. Stability profi les of drug products extended beyond labeled
epinephrine from the active L-enantiomer to the inactive expiration dates. J Pharm Sci 2006;95:1549.
D-enantiomer.15,16 One study of >100 pens that were 1-11 4. US Department of Health and Human Services. Guidance for federal
agencies and state and local governments: potassium iodide tablets shelf life
years past their expiration date and had been exposed to extension. March 2004. Available at: www.fda.gov/media/72521/download.
wide temperature ranges while stored in EMS vehicles Accessed July 16, 2020.
found that only 12.6-31.3% of the labeled dose remained.17 5. US Department of Health and Human Services. State antiviral drug stockpile
HHS update: February 11, 2020. Available at: www.fda.gov/media/135460/
download. Accessed July 16, 2020.
NALOXONE 6. G Stark et al. A study of the stability of some commercial solid dosage forms
Available as injectable solutions and nasal sprays beyond their expiration dates. Pharm J 1997;258:637.
7. R Regenthal et al. The pharmacologic stability of 35-year old theophylline.
for reversal of opioid overdose, naloxone is now widely Hum Exp Toxicol 2002;21:343.
distributed to first responders and family members of opioid 8. L Cantrell et al. Stability of active ingredients in long-expired prescription
medications. Arch Intern Med 2012;172:1685.
users, who may retain these products beyond their expiration 9. JG Schier et al. Preparing for chemical terrorism: stability of injectable
date. In a 2019 study of naloxone samples collected from atropine sulfate. Acad Emerg Med 2004;11:329.
EMS or law enforcement training supplies and returns that 10. GD Novack. Can I use those eyedrops after the expiration date? Ocul Surf
2015;13:169.
had expired between 1990 and 2018, most samples were 11. FE Simons et al. Outdated EpiPen and EpiPen Jr autoinjectors: past their
found to contain more than 90% of their labeled content.18 prime? J Allergy Clin Immunol 2000;105:1025.
12. O Rachid et al. Epinephrine doses contained in outdated epinephrine auto-
injectors collected in a Florida allergy practice. Ann Allergy Asthma Immunol
CONCLUSION 2015;114:354.
When no suitable alternative is available, outdated 13. FL Cantrell et al. Epinephrine concentrations in EpiPens after the expiration
date. Ann Intern Med 2017;166:918.
drugs may be effective. How much potency they retain varies
14. L Kassel et al. Epinephrine drug degradation in autoinjector products. J
with the drug, the formulation, the lot, the preservatives Allergy Clin Immunol Pract 2019;7:2491.
(if any), and the storage conditions, especially heat and 15. J Lan et al. Evaluation of epinephrine’s expiration date: a US Food and Drug
Administration’s perspective. J Allergy Clin Immunol Pract 2019;7:2948.
humidity. Many solid dosage formulations stored under 16. L Hollein and U Holzgrabe. Ficts and facts of epinephrine and norepinephrine
reasonable conditions in their original unopened containers stability in injectable solutions. Int J Pharm 2012;434:468.
retain ≥90% of their potency for at least 5 years after the 17. A Stonemen et al. Stability of epinephrine in expired EpiPen products from
EMS ambulances. AAPS 2014;W5370.
expiration date on the label, and sometimes much longer. 18. S Pruyn et al. Quality assessment of expired naloxone products from first-
Solutions and suspensions are generally less stable. There are responders’ supplies. Prehosp Emerg Care 2019;23:647.

Drugs In Practice

T
he FDA has approved peanut allergen powder-dnfp
Summary: Peanut Allergen Powder (Palforzia)
(Palforzia – Aimmune) for use as oral immunotherapy to
mitigate allergic reactions, including anaphylaxis, caused • Oral immunotherapy approved by the FDA to mitigate allergic
by accidental peanut exposure in patients with a confirmed reactions caused by accidental peanut exposure in patients with
peanut allergy. It is the first drug to be approved in the US peanut allergy.
for this indication; Viaskin Peanut, an immunotherapy patch, • Must be taken continuously to retain its effect and does not eliminate
is under FDA review for the same indication. the need to avoid peanut exposure or to carry an epinephrine
injector.
STANDARD TREATMENT • Significantly
improved tolerance to peanut protein exposure in
Avoidance of peanut exposure is the only way to children 4-17 years old in a double-blind, placebo-controlled trial.
completely prevent a reaction. All patients with peanut allergy • Patients receive 5 gradually increasing doses (0.5-6 mg) on day 1
should have an epinephrine injector readily available to treat a followed by up titration every 2 weeks to a maintenance dosage
of 300 mg once daily; patients must be monitored for 1 hour
serious allergic reaction.1
following the fi rst dose at each of 11 titration levels.
In high-risk infants (i.e., those with other allergic
conditions such as severe atopic dermatitis or egg allergy), • Eosinophilic esophagitis and severe anaphylaxis can occur; the
drug is contraindicated in patients with uncontrolled asthma or a
early introduction of peanut protein has been shown to history of eosinophilic GI disease.
reduce development of peanut allergy by about 80%.2 In older
children with established peanut allergy, oral immunotherapy
with compounded peanut flour formulations or commercially
available peanut products has been used to mitigate allergic with the active drug than with placebo (9.2% vs 1.0%
reactions; in a retrospective analysis of 270 children 4-18 during dose titration; 1.0% vs 0.0% during maintenance
years old who received oral immunotherapy, 79% successfully treatment).
completed dose escalation and maintained a desensitized state Anaphylaxis occurred more often with peanut allergen
with daily dosing.3 powder than with placebo during dose titration (9.4% vs
3.8%) and maintenance dosing (8.7% vs 1.7%). Severe
CLINICAL STUDY anaphylaxis occurred in 4 patients taking the drug during
Peanut allergen powder has not been compared with dose titration and in 1 taking it during maintenance
other drugs or with actual peanuts or peanut products in treatment.
clinical trials. Its efficacy was established in a randomized, In clinical trials, eosinophilic esophagitis was confirmed
double-blind trial (PALISADE) in which 496 children by biopsy in 12 patients taking peanut allergen powder (1.1%)
4-17 years old with peanut allergy (72% with a history of and in none taking placebo. Palforzia is contraindicated for
anaphylactic reaction to peanuts) were treated with peanut use in patients with a history of eosinophilic esophagitis or
allergen powder (maintenance dose 300 mg/day after 20- another eosinophilic GI disease.
40 weeks of dose titration) or placebo. Patients were then
sequentially challenged with 300, 600, and 1000 mg REMS
of peanut protein (one peanut contains about 250-300 To reduce the risk of anaphylactic death, the FDA has
mg of peanut protein). The percentage of patients who required patients who receive Palforzia to enroll in a Risk
tolerated each challenge without dose-limiting symptoms Evaluation and Mitigation Strategy (REMS) program and
was significantly higher in the Palforzia group than in the healthcare providers, healthcare settings, and pharmacies that
placebo group Table 1.4 prescribe, administer, or dispense the drug to be certified.
ADVERSE EFFECTS DOSAGE, ADMINISTRATION, AND COST

The most common adverse effects reported with use Palforzia is indicated for use in children 4-17 years
of peanut allergen powder in the PALISADE trial and old; maintenance treatment can be continued in patients
an unpublished 24-week safety trial (RAMSES) were ≥18 years old. Treatment should not be started in patients
abdominal pain, vomiting, nausea, cough, rhinorrhea, throat who have had severe or life-threatening anaphylaxis within
irritation, sneezing, urticaria, and skin and mouth pruritus. the previous 60 days. Because asthma increases the risk
Discontinuation due to adverse effects was more common of death in patients experiencing anaphylaxis, Palforzia is
Drugs In Practice
Table 1 – PALISADE Trial Results1

Treatment Exposure Tolerance Rate2
300 mg 600 mg 1000 mg
Peanut allergen powder (n=372) 76.6% 67.2% 50.3%
Placebo (n=124) 8.1% 4.0% 2.4%
1. PALISADE Group of Clinical Investigators et al. N Engl J Med 2018;379:1991.

2. Defined as the ability to ingest a single dose of the indicated amount of peanut protein during the exit food challenge with no dose-limiting symptoms (based on
clinical judgement). At all doses, peanut allergen powder met prespecified criteria for superiority vs placebo.
contraindicated in patients with uncontrolled asthma. The room-temperature semi-solid food such as applesauce,
drug should be withheld during acute asthma exacerbations pudding, or yogurt.
and should be discontinued in patients with recurrent Pharmacoeconomic analyses have suggested that
exacerbations or persistent loss of asthma control. the drug is not cost-effective relative to peanut avoidance
Palforzia dosing consists of three phases: initial dose alone.5-7
escalation, up-dosing, and maintenance. During initial
dose escalation, patients are given increasing doses of CONCLUSION
peanut allergen powder (0.5, 1, 1.5, 3, and 6 mg) 20-30 Oral immunotherapy with peanut allergen powder
minutes apart in a single day in a healthcare setting. Patients (Palforzia) significantly improved tolerance to peanut
should be observed for at least 1 hour after the last dose. protein exposure in children with peanut allergy in one
Patients who tolerate the 3-mg dose during initial dose clinical trial. Palforzia can cause serious allergic reactions
escalation can move to the up-dosing phase, which consists including anaphylaxis. It must be taken continuously to
of 11 gradually increasing doses (ranging from 3 to 300 mg) retain its effect and it does not eliminate the need to avoid
taken once daily for 2 weeks each. The first dose at each level peanut exposure or to carry an epinephrine injector. How
should be administered in a healthcare setting and patients maintenance treatment with other peanut products or with
should be monitored for 1 hour after taking the drug. actual peanuts would compare to use of this very expensive
The recommended maintenance dosage of Palforzia is product is unknown.
300 mg once daily. The drug must be taken continuously to
retain its effect. References:
Treatment with Palforzia does not eliminate the need 1. CDC. Voluntary guidelines for managing food allergies in schoos and early
to carry an epinephrine injector for emergency use. Allergic care and education programs. 2013. Available at: http://bit.ly/39Y4H5O.
reactions may be more likely to occur with exercise, hot water Accessed February 27, 2020.
2. G Du Toit et al. Randomized trial of peanut consumption in infants at risk for
exposure, or concurrent NSAID use, or during intercurrent peanut allergy. N Engl J Med 2015; 372:803.
illness (e.g., a viral infection), fasting, menstruation, or 3. RL Wasserman et al. Real-world experience with peanut oral immunotherapy:
sleep deprivation. Patients who miss 1 or 2 doses can resume lessons learned from 270 patients. J Allergy Clin Immune Pract 2019; 7:418.
treatment at the same dose level. No data are available on 4. PALISADE Group of Clinical Investigators et al. AR101 oral immunotherapy
for peanut allergy. N Engl J Med 2018; 379:1991.
resumption of treatment after ≥3 missed doses. 5. List price according to the manufacturer.
Palforzia is supplied in capsules containing 0.5, 1, 10, 6. M Shaker and M Greenhawt. Estimation of health and economic benefits of
20, or 100 mg of peanut allergen powder and in sachets commercial peanut immunotherapy products: a costeffectiveness analysis.
JAMA Netw Open 2019; 2:e193242.
containing 300 mg of powder; both should be stored in the
7. Institute for Clinical and Economic Review. Oral immunotherapy and
refrigerator. To administer a dose, the capsules or sachets Viaskin® Peanut for peanut allergy: effectiveness and value. 2019. Available
should be opened and the powder sprinkled over cold or at: http://bit.ly/37h4NUu. Accessed February 27, 2020.

Spot The Diagnosis
Test Your Diagnostic Skills
Quiz # 34 Answer
B. Staphylococcal impetigo
(Quiz # 34 Question is published in this issue on page 25)
DIscussion
This patient had staphylococcal impetigo, B, that was spread by shaving. He was treated with intranasal mupirocin for the
presumed nasal carrier state and was also given an oral antibiotic to cover for methicillin-resistant Staphylococcus aureus. The
rash resolved uneventfully.
Candida infection could resemble this patient’s rash, although it would be unusual in an otherwise healthy person. Neither
acne nor rosacea would be expected to present in this manner over a 1-week period. Contact dermatitis is not typically pustular
and is usually pruritic.
Contd... from page 37

mineral metabolism in CKD. New York, NY: National Kidney Foundation; https://doi.org/10.1111/j.1744-9987.2007.00489.x.
2006. p 31-41. 5. Cruzado JM, Moreno P, Torregrosa JV, et al. A randomized study
3. Oltmann SC, Madkhali TM, Sippel RS, Chen H, Schneider DF. KDIGO comparing parathyroidectomy with cinacalcet for treating hypercalcemia
guidelines and parathyroidectomy for renal hyperparathyroidism.J Surg Res in kidney allograft recipients with hyperparathyroidism. J Am Soc Nephrol
2015 Nov;199(1):115-20. DOI: https://doi.org/10.1016/j.jss.2015.04.046. 2016;27(8):2487-94. DOI: https://doi.org/10.1681/ASN.2015060622.
4. Tominaga Y, Matsuoka S, Sato T, et al. Clinical features and hyperplastic
pattern of parathyroid glands in hemodialysis patients with advanced Disclaimer: Originally published as Arora S, Jahufar F. Image diagnosis:
secondary hyperparathyroidism refractory to maxacalcitol treatment and Disappearing digits: Metabolic bone disease in end-stage renal disease. Perm J
required parathyroidectomy. Ther Dial Apher 2007 Aug;11(4):266-73. DOI: 2019;23:18-177. DOI: https://doi.org/10.7812/TPP/18-177


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Vol 11 No 4, July, 2020 A CME Journal for Family Physicians

33 Vitamin D Supplements Don't Prevent Cancer or

20 COVID Round Up 25 Spot The Diagnosis 27 X-Ray Tutorial 35 What’sYour Diagnosis?

Follow us on at: https://www.facebook.com/gpclinics.in

For the use of a Registered Medical Practitioner or a Hospital or Laboratory only

2 GP Clinics Vol 11 No 4, July, 2020

Vol 11 No 4, July, 2020 GP Clinics 5

Seventeen speciality departments.

Empowering Your Practice

OCULAR MANIFESTATIONS OF DIABETES

21 Existing Drugs, Respiratory Droplets

The Folly of Ordering, Then Ignoring, Radiographs

Vol 11 No 4, July, 2020 GP Clinics 7

Empowering Your Practice

How Important is Glucagon in the Pathophysiology of Diabetes?

WHAT’S THE “TAKE HOME”? 31

A Family with a Variety of “Flu” Symptoms

8 GP Clinics Vol 11 No 4, July, 2020

Empowering Your Practice

Vitamin D Supplements Don't Prevent Cancer or Heart Disease

What's Your Diagnosis?, 35

Multiple Cutaneous Nodules in a Previously Healthy Male

Disappearing Digits: Metabolic Bone Disease in End-Stage

MICHAEL J. BLOCH, MD LAWRENCE I. KAPLAN, MD GREGORY W. RUTECKI, MD

MARTHA FUNNELL, MS, RN, CDE RONALD N. RUBIN, MD

www.consultant360.com • January 2018 • CONSULTANT 3

10 GP Clinics Vol 11 No 4, July, 2020

DR YESHWANT K AMDEKAR DR NH BANKA

PROF (DR) DG SAPLE Prof JC Suri

DR RAM PRABHOO DR SHASHANK R JOSHI

DR UMESH KHANNA DR AGAM VORA

DR MAKARAND DAMLE DR MANOJ SHARMA

DR KETAN MEHTA DR MAHESH C GOEL

Vol 11 No 4, July, 2020 GP Clinics 11

type 1 diabetes, 40% of people with type

HOW DIABETES AFFECTS THE EYE

Vol 11 No 4, July, 2020 GP Clinics 15

litus type 1 develop DME within 9 years

OCULAR SIGNS OF DIABETIC RETINOPATHY

16 GP Clinics Vol 11 No 4, July, 2020

with sharp margins (Figures 2, 3, and 5).

Vol 11 No 4, July, 2020 GP Clinics 17

patient has high-risk PDR and may be a

treatment and risk of complications in patients

Vol 11 No 4, July, 2020 GP Clinics 19

21 Existing Drugs, Respiratory Droplets

recently published scientific literature. It includes sections

New Data Indicate Remdesivir May Reduce Hospital Stay

the study wrote. “However, given high mortality despite the

Vol 11 No 4, July, 2020 GP Clinics 21

The Folly of Ordering, Then Ignoring,

22 GP Clinics Vol 11 No 4, July, 2020

What’s the “Take Home”?

24 GP Clinics Vol 11 No 4, July, 2020

What does this look like to you?

See answer and discussion on page No 42

How Important is Glucagon in the

26 GP Clinics Vol 11 No 4, July, 2020

Case 10 Clinical history

Intrepretation on the next page...

Clear left lung

Clear right heart border